1. Field of the Invention
The present invention relates generally to the field of medicine and more specifically to the use of a substituted 1,3-benzodioxole to reduce a wasting condition in a subject.
2. Background Information
Various pathologic, physiologic and metabolic states in a subject can produce a wasting condition that is characterized, in part, by a progressive loss of body, organ or tissue mass. A wasting condition can occur as a result of a pathology such as cancer or can be due to a physiologic or metabolic state such as the disuse deconditioning that can occur, for example, due to prolonged bed rest or to the weightlessness associated with space flight.
In most cases, minimal loss of body mass is of little concern. For example, a minimal loss of body mass can occur in a subject having a brief illness but an otherwise normal nutritional status. In this case, the lost body mass is quickly regained after the illness runs its course. Loss of body mass can become critical, however, during a prolonged illness, where nutritional depletion can occur, or when a weight bearing load is removed from the musculo-skeletal system for an extended period of time. Removal of a weight bearing load can occur, for example, due to long term bed rest, immobilization of a limb or simulated or actual weightlessness such as during space flight.
The loss of body mass that occurs during a wasting condition can be characterized by a loss of total body weight, a loss of organ weight such as a loss of bone or muscle mass or to a decrease in tissue protein. In addition, the loss of body mass associated with a wasting condition can be localized or systemic. For example, localized loss of body mass can occur due to denervation of a muscle or to the disuse deconditioning that occurs when a limb is immobilized in a cast. Systemic loss of body mass can result, for example, due to the disuse deconditioning that occurs during space flight or due to a pathology such as cancer.
A wasting condition, if unabated, can have dire health consequences. For example, the changes that occur during a wasting condition can lead to a weakened physical state that is detrimental to an individual's health. The severe wasting or cachexia associated with cancer, for example, can prolong patient convalescence and decrease the patient's quality of life.
Three general approaches have been utilized to reduce a wasting condition in a subject. One approach has been to alter the systemic stress response that is induced due to acute injury or illness. For example, an attempt has been made to manipulate the signals mediated by cytokines or lipids, which are involved in regulating the stress response.
Another approach to reduce a wasting condition has been to administer supplemental nutrition. In many cases, however, even when a subject is maintained on a program of total parenteral nutrition over several weeks, loss of body mass continues and no increase in muscle mass occurs. Thus, simple replacement of any deficient caloric intake is insufficient, alone, to alleviate an undesirable loss of body mass.
Nutritional supplementation has been used in combination with the administration of anabolic agents in an attempt to reduce wasting. This combined approach currently is the preferred method of treatment and can effectively counteract the loss of body mass that occurs due to acute illness, disuse deconditioning and cachexia.
Various anabolic agents, including anabolic steroids, growth hormone, insulin-like growth factors and beta adrenergic agonists, have been used in the combined modality protocol. Unfortunately, the usefulness of anabolic agents is limited by undesirable side effects. For example, anabolic steroids can cause adverse effects in the liver and in the cardiovascular and reproductive systems of a treated individual and can affect the psychological status of the subject. Other anabolic agents such as growth hormone and insulin-like growth factors can induce diabetes, hypothyroidism and arthritis as well as acromegaly, which is associated with myopathy, peripheral neuropathy and cardiac disease.
The .beta.2 adrenergic agonists clenbuterol and salbutamol are anabolic agents that can reduce weight loss, particularly loss of muscle mass and bone density (see Kim and Sainz, Life Sci. 50:397-407 (1992)). However, .beta.2 agonists can produce undesirable side effects, including increased heart rate, decreased blood pressure or muscle tremor, in a treated subject. These agents also can produce undesirable behavioral changes. Thus, a need exists to identify pharmaceutical agents that effectively reduce a wasting condition in a subject without producing significant adverse side effects. The present invention satisfies this need and provides related advantages as well.